Cannabinoid-Mediated Epigenetic Regulation of Immune Functions

Abstract

The cannabinoid system consisting of exogenous and endogenous ligands as well as dedicated receptors has been proposed to play a regulatory role in immune functions. The exogenous cannabinoid Δ9-tetrahydrocannabinol (THC), one of the most widely studied marijuana derivatives, has been associated with multiple anti-inflammatory properties over the years. The majority of THC research has centered on the shift from Th1 to Th2 responses however, the complexity of inflammation has since increased. Recent studies have revealed that epigenome, Th cell subsets, and immunoregulatory cell induction, are all known to impact inflammation. In the current research, we have attempted to look holistically at the impact of THC on inflammation, specifically addressing its effect on epigenome and regulatory cells such as myeloid derived suppressor cells (MDSCs). In regards to epigenetic regulation, we found that THC altered both DNA methylation profiles and microRNA (miRNA, miR) expression in immune cells. THC treatment decreased DNA methylation of key genes, STAT3 and arginase1 (Arg1), associated with the induction and suppressive capabilities of myeloid derived suppressor cells (MDSCs). Furthermore, THC treatment triggered alterations in miRNA expression in lymphocytes, decreasing the differentiation of Th1, via overexpression of miR-29b, and Th17, via reduced miR-21 expression. Moreover, we discovered that THC, a ligand for both CB1 and CB2 cannabinoid receptors, required a fully functional CB1 receptor for optimal induction of MDSCs. Additionally, functional CB1 receptor was necessary for THC to inhibit the Th1 driven proinflammatory response associated with host versus graft disease (HvGD) leading to allogenic graft survival. In order to assess THC inhibition of inflammation, driven by Th1 and Th17, we also used delayed type hypersensitivity (DTH). In this model, THC was able to reduce both Th1 and Th17 associated cytokines and transcription factors. We have further highlighted the importance of the endocannabinoid (EC) system in immunoregulation through the therapeutic use of the endogenous cannabinoid receptor ligand 2-arachidonoyl glycerol (2-AG) and detection of 2-AG during an ongoing DTH response.

The impact of endogenous and exogenous cannabinoids and the CB receptors on expressed on immune cells on the regulation of immune response is an exciting area of research with potential implications in the prevention and treatment of inflammatory and autoimmune diseases. Taken together, our findings demonstrate for the first time how cannabinoids can regulate the immune response through alterations in the epigenetic and immunoregulatory pathways, thereby controlling inflammation driven by Th1 and Th17 cells. Our studies shed new light on how cannabinoid system can be targeted to therapeutically prevent and treat inflammatory and autoimmune diseases.